The present invention relates to a system and a method for quantitatively assessing diabetic cardiac autonomic neuropathy (DCAN) in type I diabetic biological subject. More particularly, the present invention relates to a system and a method for quantitatively assessing DCAN in type I diabetic biological subject based on Principal Dynamic Mode (PDM) analysis.
DCAN is one of the most overlooked of all serious diabetes complications, and it can cause abnormalities in heart rate control as well as central and peripheral vascular dynamics. Consequences of DCAN include exercise intolerance, intraoperative cardiovascular lability, orthostatic hypotension, myocardial ischemia, increased risk of mortality and morbidity, and reduced quality of life, for persons with diabetes. One useful noninvasive method to assess autonomic function in various physiological and pathophysiological conditions, including evaluation of the autonomic dysfunction in diabetic subjects, is the use of heart rate variability (HRV). HRV is a marker of sympathetic and parasympathetic (vagal) influences on the modulation of heart rate. Reduced heart rate variability is known to be one of the earliest indicators of DCAN as DCAN has been shown to involve an imbalance of the autonomic nervous system (ANS). A recent study examining the effect of sustained hyperinsulinemic hypoglycemia on cardiovascular autonomic regulation in type I diabetics and their non-diabetic counterparts has found reduced cardiac vagal outflow in all patients. Another study, examining HRV changes in diabetes, has found that decreases in autonomic function are present early in the development of diabetes and that diabetes leads to a progressive decline in autonomic function. Whereas the DCAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group identified heart rate variability, baroreflex sensitivity, muscle sympathetic nerve activity, plasma catecholamines, and heart sympathetic imaging as the most sensitive and specific approaches currently available to evaluate DCAN in clinical research, it also identified serious limitations of the existing methods and emphasized that efforts should be undertaken to develop new non-invasive and safe DCAN tests, with a higher sensitivity and specificity.
The limitations of the existing methods for evaluation of DCAN are clearly seen in experimental studies. For example, young streptozotocin (STZ)-diabetic rats exhibit a significant reductions in both heart rate and HRV, suggesting disturbance in the ANS balance. Further, insulin treatment of these STZ-treated diabetic rats showed no significant recovery of the autonomic nervous activity even though heart rate recovered to the state recorded prior to STZ administration. This is in agreement with clinical studies identifying limitations of heart rate variability as a diagnostic marker of DCAN. Apparently, new quantitative methods for assessment of this diabetic complication are needed.
In recent years, multiple, quite sophisticated, studies of pathogenetic mechanisms of diabetic peripheral neuropathy were conducted in mouse models, in contrast, investigations of DCAN leading to discovery of the important roles of the sorbitol pathway of glucose metabolism, impaired neurotrophic support, and mitochondrial dysfunction and bioenergetics have been performed in the rat. The literature on DCAN in mice is sparse, although a recent study in streptozotocin-diabetic mice identified the important role for the cyclooxygenase pathway. One intriguing mouse model of Type I diabetes is the Akita mouse. Ins2C96Y Akita mice, which spontaneously develop insulin-dependent diabetes at about 4 weeks of age, express a mutant non-functional insulin isoform. Four month-old Akita mice displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, tactile allodynia, as well as gait disturbances, in addition to sensory neuropathy, 5 month-old Akita mice develop motor nerve conduction velocity deficit and axonal atrophy of large myelinated fibers (dropout of large axons). Akita mice also show markedly impaired corpus cavernosum nitrergic nerve and sinusiodal endothelium function. Dystrophic changes have been noted for superior mesenteric and celiac ganglia. A further investigation provided evidence for cardiac parasympathetic dysfunction. Thus, there is a strong rationale to suggest that Akita mice develop DCAN similar to those found in STZ-diabetic rodents, and can be a suitable model for studying this complication.